DK170248B1 - Sulfonated 4-demethyl-13-dioxolanyl-daunomycinone, 4-demethoxy-4- (protected amino) -13-dioxolanyl-daunomycinone, and process for preparing 4-demethoxy-daunomycinone, the aglycone of 4-demethoxy-daunorubicin - Google Patents
Sulfonated 4-demethyl-13-dioxolanyl-daunomycinone, 4-demethoxy-4- (protected amino) -13-dioxolanyl-daunomycinone, and process for preparing 4-demethoxy-daunomycinone, the aglycone of 4-demethoxy-daunorubicin Download PDFInfo
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- DK170248B1 DK170248B1 DK063889A DK63889A DK170248B1 DK 170248 B1 DK170248 B1 DK 170248B1 DK 063889 A DK063889 A DK 063889A DK 63889 A DK63889 A DK 63889A DK 170248 B1 DK170248 B1 DK 170248B1
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- C07C50/38—Quinones containing —CHO or non—quinoid keto groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C46/00—Preparation of quinones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings
- C07C2603/42—Ortho- or ortho- and peri-condensed systems containing four condensed rings containing only six-membered rings
- C07C2603/44—Naphthacenes; Hydrogenated naphthacenes
- C07C2603/46—1,4,4a,5,5a,6,11,12a- Octahydronaphthacenes, e.g. tetracyclines
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Abstract
Description
i DK 170248 B1in DK 170248 B1
Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af 4-demethoxydaunomycinon med formlen I: O OH o" ' w o OH 6h 10 4-Demethoxydaunorubicin, som er en analog til det kendte antibiotikum, daunorubicin, er et glycosid dannet ud fra et tetracykllsk aglycon (+) 4-demethoxydaunomycinon (I) og aminosukkeret daunosamin.The present invention relates to a particular process for the preparation of 4-demethoxydaunomycinone of Formula I: O OH o "wo OH 6h 10 4-Demethoxydaunorubicin, which is an analogue of the known antibiotic, daunorubicin, is a glycoside formed from a tetracyclic aglycone (+) 4-demethoxydaunomycinone (I) and amino sugar daunosamine.
Dens anvendelighed som en kraftig antitumorforbindelse er beskrevet i Cancer Treatment Report 60 (7): 829-834 (1976) og ibidem 61 (5): 893-894 15 (1977).Its utility as a potent antitumor compound is described in Cancer Treatment Report 60 (7): 829-834 (1976) and ibidem 61 (5): 893-894 (1977).
En syntese af (+) 4-demethoxydaunomycinon er beskrevet i US-A-4046878. En anden syntese er baseret på fremstillingen af racemisk 1,4-dimethoxy-6-hydroxy-6-acetyltetralin, dets optiske spaltning, kondensation af (-) enantiomeren med phthalsyreanhydrid og stereoselektiv 20 indføring af OH-gruppen i position 7 (se US-A-4077988 og US-A-4132721). Ifølge den foreliggende opfindelse er der tilvejebragt en fremgangsmåde til fremstilling af 4-demethoxy-daunomycinon med formel IA synthesis of (+) 4-demethoxydaunomycinone is described in US-A-4046878. Another synthesis is based on the preparation of racemic 1,4-dimethoxy-6-hydroxy-6-acetyltetralin, its optical cleavage, condensation of the (-) enantiomer with phthalic anhydride, and stereoselective introduction of the OH group at position 7 (see U.S. Pat. A-4077988 and US-A-4132721). According to the present invention, there is provided a process for the preparation of 4-demethoxy daunomycinone of formula I
p OH o 25 o oh Bh 1 hvilken fremgangsmåde er ejendommelig ved, at man 30 (a) beskytter 13-ketogruppen i 4-demethyldaunomycinon med formel (2): . .p OH o 25 o oh Bh 1 which is peculiar to protecting the 13-keto group of 4-demethyldaunomycinone of formula (2):. .
2 DK 170248 B1 ved behandling med ethylenglycol, (b) omsætter det resulterende 4-demethyl-13-dioxolanyldaunomycinon med formel (3): 5 ο «μ i-i H fH 0 0 i 3In treatment with ethylene glycol, (b) the resulting 4-demethyl-13-dioxolanyldenomycinone of formula (3): 5 ο «μ i-i H fH 0 0 i 3
M 0 ΪΗ CMM 0 ΪΗ CM
10 med et sulfonylchlorid med formlen II: R-S02C1 (II) 15 hvori R betegner en eventuelt med ét eller flere halogenatomer substitueret al kylgruppe med 1 til 10 carbonatomer, eller en eventuelt med halogen, alkyl, alkoxy eller nitro substitueret arylgruppe, i nærværelse af N,N-di isopropyl ethyl amin og en katalytisk mængde 4-dimethylamino-pyri-20 din, (c) omsætter det resulterende sulfonerede 4-demethyl-13-dioxolanyl-daunomycinon med formel (4): o tlH Γ1 RS0TYikV 4 30 hvori R har den ovenfor anførte betydning, med en amin med formel III: * R1(R2)CH-NH2 (III) * 1 2 35 hvori R og R uafhængigt af hinanden betegner et hydrogenatom eller en phenylgruppe substitueret med én eller flere alkoxygrupper, i opløsning, (d) fjerner amino-beskyttelsesgruppen fra det resulterende 4-de-methoxy-4-(beskyttet amino)-13-dioxolanyl-daunomycinon med formlen (5): DK 170248 Bl 3 I-1 o nH o o10 with a sulfonyl chloride of formula II: R-SO2C1 (II) wherein R represents an optionally substituted with one or more halogen atoms of one or more carbon groups of 1 to 10 carbon atoms, or an optionally with halogen, alkyl, alkoxy or nitro substituted aryl group, in the presence of N, N-di isopropyl ethyl amine and a catalytic amount of 4-dimethylamino-pyridine, (c) reacting the resulting sulfonated 4-demethyl-13-dioxolanyl-daunomycinone of formula (4): o to 1H1 RS0TYikV 4 30 wherein R is as defined above, with an amine of formula III: * R 1 (R 2) CH-NH 2 (III) * wherein R and R are independently a hydrogen atom or a phenyl group substituted by one or more alkoxy groups, in solution, (d) removing the amino protecting group from the resulting 4-de-methoxy-4- (protected amino) -13-dioxolanyl-daunomycinone of formula (5): DK 170248 Bl 3 I-1 o nH oo
, i« ,» h OH, i «,» h OH
R-CH-RR-CH-R
1 2 hvori R og R har den ovenfor anførte betydning, 10 (e) diazoterer 4-aminogruppen i det resulterende 4-demethoxy-4- aminodaunomycinon med formel (6): o o« o 15 6Wherein R and R are as defined above, (e) diazotizes the 4-amino group of the resulting 4-demethoxy-4-aminodaunomycinone of formula (6):
0 OH OH0 OH OH
og (f) reducerer det resulterende diazoderivat med formel (7): 20 o oH oand (f) reduces the resulting diazo derivative of formula (7): 20 o oH o
25 V o OH OH25 V o OH OH
med hypophosphorsyrling i vandig opløsning, for derved at opnå 4-demeth-oxydaunomycinon med formel I.with hypophosphoric acid in aqueous solution to obtain 4-demethoxydaunomycinone of formula I.
30 4-Demethyl-daunomycinonet med formel (2) kan fremstilles ved deme-thylering af daunomycinon med formel (1): jj OH o 35 1 OCH3 o oh g» 4 DK 170248 B1The 4-demethyl daunomycinone of formula (2) can be prepared by demethylation of daunomycinone of formula (1): 1H OH o 35 1 OCH 3 o g »4 DK 170248 B1
Der er derfor tilvejebragt en fremgangsmåde, der kan påbegyndes med. det naturligt forekommende (+) daunomycinon, som er mere effektiv og kræver færre trin end den samlede kemiske syntese. Ydermere kræver fremgangsmåden hverken optisk spaltning eller kemiske rensningstrin.Therefore, a method which can be started is provided. the naturally occurring (+) daunomycinone, which is more effective and requires fewer steps than the overall chemical synthesis. Furthermore, the process requires neither optical decomposition nor chemical purification steps.
5 Opfindelsen angår desuden de hidtil ukendte forbindelser med formlerne (4) og (5).The invention further relates to the novel compounds of formulas (4) and (5).
Den foreliggende fremgangsmåde er illustreret ved følgende reaktionsskema (Skema 1). Udgangsmaterialet til fremgangsmåden kan være (+) daunomycinon (1). Dette kan fremstilles ved en passende hydrolyse af 10 daunorubicin, der i sig selv er udvundet ved fermentering som beskrevet i US-A-4012284. Daunomycinon kan demethyleres ved behandling med AlCl3 i et inert organisk opløsningsmiddel, såsom nitrobenzen, ved tilbagesvalingstemperaturen til opnåelse af 4-demethyldaunomycinon, der også kaldes carminomycinon (2). En sådan fremgangsmåde er beskrevet i US-A-15 4188377.The present process is illustrated by the following reaction scheme (Scheme 1). The starting material for the process may be (+) daunomycinone (1). This can be prepared by a suitable hydrolysis of 10 daunorubicin, which is itself recovered by fermentation as described in US-A-4012284. Daunomycinone can be demethylated by treatment with AlCl3 in an inert organic solvent, such as nitrobenzene, at the reflux temperature to give 4-demethyldaunomycinone, also called carminomycinone (2). Such a process is described in US-A-15 4188377.
Trin (a) udføres ved behandling med ethylenglycol, fortrinsvis under tilstedeværelse af p-toluensul fonsyre ved tilbagesvalingstemperaturen. Den resulterende forbindelse (3) sulfoneres i trin (b) ved C4-0H-stillingen til opnåelse af forbindelse (4), uden at nogen af de tilbage-20 bievne OH-grupper beskyttes. Sulfoneringsmidlet er et sulfonylchlorid med formel II: R-S02C1 (II) 25 hvori R betegner en al kyl gruppe med 1 til 10 carbonatomer, en sådan halogen- eller polyhalogensubstitueret alkylgruppe, eller en arylgruppe, der eventuelt er substitueret med mindst én, for eksempel fra én til tre, substituenter udvalgt blandt halogenatom/-atomer og alkyl, såsom Cj-C^ alkyl, alkoxy, såsom Cj-C^ alkoxy og nitrogrupper. Foretrukne 30 grupper, som R kan betegne er: 4-fluorphenyl og 4-tolyl. Reaktionen udføres fortrinsvis i pyridin. Det bør fremhæves at denne selektive sulfonylering alene under betingelserne ifølge opfindelsen, det vil sige * * omsætning af 4-demethyl-daunomycinonderivatet (3) med sulfonylchloridet ved tilstedeværelse af N,N-di isopropyl ethylamin og en katalytisk mængde * 35 4-dimethyl amino pyridin, ikke berører hverken de phenoliske C6-0H og C11-0H eller det benzyliske C7-0H.Step (a) is carried out by treatment with ethylene glycol, preferably in the presence of p-toluenesulphonic acid at the reflux temperature. The resulting compound (3) is sulfonated in step (b) at the C4-0H position to give compound (4) without protecting any of the residual OH groups. The sulfonating agent is a sulfonyl chloride of formula II: R-SO2 Cl (II) wherein R represents an alkyl group having 1 to 10 carbon atoms, such a halogenated or polyhalogen substituted alkyl group, or an aryl group optionally substituted by at least one, for example from one to three, substituents selected from halogen atom (s) and alkyl such as C 1 -C 4 alkyl, alkoxy such as C 1 -C 3 alkoxy and nitro groups. Preferred groups which R may denote are: 4-fluorophenyl and 4-tolyl. The reaction is preferably carried out in pyridine. It should be noted that this selective sulfonylation only under the conditions of the invention, i.e., * reaction of the 4-demethyl-daunomycinone derivative (3) with the sulfonyl chloride in the presence of N, N-di-isopropyl ethylamine and a catalytic amount of * 35 4-dimethyl amino pyridine, does not affect either the phenolic C6-0H and C11-0H or the benzyl C7-0H.
5 DK 170248 B15 DK 170248 B1
Skema 1Scheme 1
Jj OH j| Jt” 8 5Jj OH j | Jt ”8 5
“Ό> 5h gH OM O ΪΗ éH“Ό> 5h gH OM O ΪΗ éH
l / i 10 / / 1/l / i 10 / / 1 /
R'S0T H §HR'S0T H §H
3 y/ i 20 o oH o o3 y / i 20 o oH o o
CpjfoPi^CpjfoPi ^
25 , «Η ΥίίΓδΗ °H25, «Η ΥίίΓδΗ ° H
R-CH-R nh2 O OH oh 5 / 6 q OH 0R-CH-R nh2 O OH oh 5/6 q OH 0
35 ' 7 (g^éCK35 '7 (g ^ éCK
N,+ O oH oH t"N, + O oH oH t "
1 o oH oH1 o oH oH
z a 6 DK 170248 B1z a 6 DK 170248 B1
Forbindelsen (4), der dannes således, behandles direkte i opløsning i trin (c) med en egnet amin med formel III: R1 5 CH-NHj m R2 1 2 hvor R og R uafhængigt af hinanden er et hydrogenatom eller en phenylgruppe substitueret med én eller flere, for eksempel fra 1-3, 10 alkoxygrupper. Alkoxygruppen/-grupperne kan have fra 1-4 carbonatomer.The compound (4) thus formed is treated directly in solution in step (c) with a suitable amine of formula III: R1 and CH2 NH2 with R212 where R and R are independently a hydrogen atom or a phenyl group substituted by one or more, for example from 1-3, 10 alkoxy groups. The alkoxy group (s) may have from 1-4 carbon atoms.
Foretrukne aminer med formel III er 4-methoxybenzylamin og 3,4-dimeth-oxybenzylamin.Preferred amines of formula III are 4-methoxybenzylamine and 3,4-dimethoxybenzylamine.
Den beskyttede amin med formel (5), kan behandles i trin (d) med trifluoreddikesyre, for eksempel i 3 timer ved stuetemperatur, for at 15 frigøre 4-aminoderivatet (6). Diazoteringen i det næste trin (e) kan udføres under anvendelse af natriumnitrit, for eksempel under anvendelse af en vandig opløsning af natriumnitrit fra 0° til 5°C. Således kan den sure opløsning fra trin (d), hvortil vand og methylenchlorid er blevet tilsat, behandles med natriumnitrit til opnåelse af diazoniumsaltet (7), 20 som kan ekstraheres i den vandige fase. Behandling af den vandige opløsning med hypophosphorsyrling, for eksempel med 50% hypophosphorsyrling, giver i trin (f) det ønskede 4-demethoxy-daunomycinon (I) af højoptisk og kemisk renhed.The protected amine of formula (5) can be treated in step (d) with trifluoroacetic acid, for example for 3 hours at room temperature, to release the 4-amino derivative (6). The diazotization in the next step (s) can be carried out using sodium nitrite, for example using an aqueous solution of sodium nitrite from 0 ° to 5 ° C. Thus, the acidic solution of step (d) to which water and methylene chloride have been added can be treated with sodium nitrite to give the diazonium salt (7), which can be extracted in the aqueous phase. Treatment of the aqueous solution with hypophosphoric acid, for example with 50% hypophosphoric acid, yields in step (f) the desired 4-demethoxy daunomycinone (I) of high optical and chemical purity.
4-Demethoxy-daunomycinon er aglycon-delen af det nyttige antitumor-25 middel, 4-demethoxy-daunorubicin. 4-demethoxy-daunorubicin med formel IV4-Demethoxy-daunomycinone is the aglycone moiety of the useful antitumor agent, 4-demethoxy-daunorubicin. 4-demethoxy daunorubicin of formula IV
»[QQsO™' " eller et farmaceutisk acceptabelt salt deraf, kan fremstilles ved, at * 35 man omsætter 4-demethoxy-daunomycinon med formel I, der er blevet fremstillet ved fremgangsmåden ifølge opfindelsen, med et egnet sukkerderivat og, om ønsket, omdanner det således opnåede 4-demethoxy-daunorubicin til et farmaceutisk acceptabelt salt deraf."[QQsO ™" or a pharmaceutically acceptable salt thereof can be prepared by reacting 4-demethoxy-daunomycinone of formula I prepared by the process of the invention with a suitable sugar derivative and, if desired, converting the 4-demethoxy daunorubicin thus obtained to a pharmaceutically acceptable salt thereof.
7 DK 170248 B17 DK 170248 B1
Sukkerderivatet kan have formlenThe sugar derivative may have the formula
Hal ' -Hal '-
RR
hvor Hal betegner et halogenatom, R4 betegner en beskyttet hydroxygrup-5 pe, og R betegner en beskyttet aminogruppe. Beskyttelsesgrupperne fjernes efter reaktion med 4-demethoxy-daunomycinonet. Hal er fortrinsvis et 10 chloratom. Hydroxygruppen kan være beskyttet med en tri fluoracetyl gruppe. Aminogruppen kan også være beskyttet med en tri fluoracetyl gruppe.where Hal represents a halogen atom, R 4 represents a protected hydroxy group, and R represents a protected amino group. The protecting groups are removed after reaction with the 4-demethoxy daunomycinone. Hal is preferably a chlorine atom. The hydroxy group may be protected by a tri-fluoroacetyl group. The amino group may also be protected by a trifluoroacetyl group.
Det resulterende 4-demethoxy-daunorubicin eller farmaceutisk acceptable salt deraf, kan formuleres fx til brug som et antibiotikum eller som et antitumormiddel, som et farmaceutisk præparat omfattende en far-15 maceutisk acceptabel bærer eller diluent.The resulting 4-demethoxy daunorubicin or pharmaceutically acceptable salt thereof may be formulated, for example, for use as an antibiotic or as an antitumor agent, as a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent.
De følgende eksempler 2-5 illustrerer opfindelsen, idet eksempel 1 belyser fremstilling af udgangsmaterialet.The following Examples 2-5 illustrate the invention, Example 1 illustrating preparation of the starting material.
Eksempel 1. 4-Demethyldaunomycinon (2) 20 Til en opløsning af 15,04 g (37,8 mmol) daunomycinon (1) i 1,4 1 methylenchlorid i en nitrogenatmosfære, blev der, under omrøring, tilsat 52,8 g (396,4 mmol) vandfrit aluminiumchlorid portionsvis i løbet af 1,5 time. Reaktionsblandingen til bagesval edes i én time, hvorefter opløsningsmidlet blev afdestilieret. En opløsning af 22,8 g (25,4 mmol) oxal-25 syre i 200 ml vand afkølet ved 0°C, blev forsigtigt tilsat remanensen og blandingen blev omrørt i 2 timer ved stuetemperatur. Det faste stof blev udvundet ved filtrering og vaskedes med vand. Produktet blev ikke yderligere renset og viste sig ved HPLC-analyse, at være 83% rent.Example 1. 4-Demethyldaunomycinone (2) To a solution of 15.04 g (37.8 mmol) of daunomycinone (1) in 1.4 l of methylene chloride in a nitrogen atmosphere was added, with stirring, 52.8 g ( 396.4 mmol) anhydrous aluminum chloride in portions over 1.5 hours. The reaction mixture was refluxed for one hour, after which the solvent was distilled off. A solution of 22.8 g (25.4 mmol) of oxalic acid in 200 ml of water cooled at 0 ° C was gently added to the residue and the mixture was stirred for 2 hours at room temperature. The solid was recovered by filtration and washed with water. The product was not further purified and, by HPLC analysis, was found to be 83% pure.
HPLC analyse: 30 Søjle: MERCK RP 18 / 7 fm (250 x 4,2 mm),HPLC analysis: 30 Column: MERCK RP 18/7 sc (250 x 4.2 mm),
Mobil fase: A - 0,01 M natriumheptansulfonat / 0,02 M phosphorsyre 6Mobile phase: A - 0.01 M sodium heptane sulfonate / 0.02 M phosphoric acid 6
Acetonitril 4 B - Methanol 7 35 Acetonitril 3Acetonitrile 4 B - Methanol 7 Acetonitrile 3
Gradient: fra 20% B til 70% B i 25 min.,Gradient: from 20% B to 70% B for 25 minutes,
Strømningshastighed: 1,5 ml/min.,Flow rate: 1.5 ml / min,
Detektor: UV ved 254 nm.Detector: UV at 254 nm.
DK 170248 B1 s TLC på kieselgel plade F 254 (Merck) under anvendelse af chloroform/acetone (8:2 ved volumen) Rf=0,58DK 170248 B1 s TLC on silica gel plate F 254 (Merck) using chloroform / acetone (8: 2 by volume) Rf = 0.58
Eksempel 2. 4-Demeth.yl-13-dioxolanyl-daunomycinon (3) c.Example 2. 4-Demethyl-13-dioxolanyl-daunomycinone (3) c.
5 Til en suspension i benzen (400 ml) af det rå 4-demethyldaunomy- cinon (2), fremstillet som beskrevet i eksempel 1, blev 30 ml ethylen- ^.To a suspension in benzene (400 ml) of the crude 4-demethyldaunomycinone (2) prepared as described in Example 1 was added 30 ml of ethylene.
glycol og 0,3 g p-toluensulfonsyre tilsat. Reaktionsblandingen tilbage-svaledes med azeotropisk fjernelse af vand i ca. 6 timer. Efter afkøling til stuetemperatur blev det faste stof udvundet ved filtrering og vasket 10 med vand og ethanol, til opnåelse af 11,3 g (3) (HPLC: 98,3%, betingelser som beskrevet i eksempel 1) efter tørring. Samlet udbytte fra (1): 70% VNMR 300 MHz (i CDC13): 8 - 1,42 (3H,s); 1,94 (lH,dd); 2,42 (lH,dt); 2,75 (IH,d); 3,18 (lH,dd); 4,04 (4H,s); 5,20 (lH,dd); 7,25 (lH,d); 7,65 15 (IH,t); 7,84 (lH,d); 12,18 (IH,s); 12,92 (IH,s); 13,52 (IH,s), M.S. : m/z * 428 (M+, basis top).glycol and 0.3 g of p-toluenesulfonic acid added. The reaction mixture was refluxed with azeotropic removal of water for ca. 6 hours. After cooling to room temperature, the solid was recovered by filtration and washed with water and ethanol to give 11.3 g (3) (HPLC: 98.3%, conditions as described in Example 1) after drying. Overall yield from (1): 70% VNMR 300 MHz (in CDCl3): 8 - 1.42 (3H, s); 1.94 (1H, dd); 2.42 (1H, dt); 2.75 (1H, d); 3.18 (1H, dd); 4.04 (4H, s); 5.20 (1H, dd); 7.25 (1H, d); 7.65 (1H, t); 7.84 (1H, d); 12.18 (1H, s); 12.92 (1H, s); 13.52 (1H, s), M.S. : m / z * 428 (M +, base peak).
TLC på Kiesel gel plade F 254 (Merck) ved anvendelse af chloroform/acetone (8:2 ved volumen) Rf=0,52 20 Eksempel 3. 4-Demethyl-4-p-toluensulfon.vl-13-dioxalan.v1-daunomycinon (4)TLC on Kiesel gel plate F 254 (Merck) using chloroform / acetone (8: 2 by volume) R f = 0.52 Example 3. 4-Demethyl-4-p-toluenesulfonyl-13-dioxalane.v1- daunomycinone (4)
Til en suspension i pyridin (330 ml) af 11,3 g (26,4 mmol) af (3), 22,6 ml (132 mmol) af di isopropyl ethylamin og 0,65 g (5,3 mmol) af 4-di-methylaminopyridin, blev en opløsning af 5,54 g (29 mmol) af p-toluensul fonyl chl or id i 25 ml pyridin dråbevis tilsat over en 5 minutters 25 periode. Efter omrøring i 15 minutter ved stuetemperatur var reaktionen tilendebragt.To a suspension in pyridine (330 ml) of 11.3 g (26.4 mmol) of (3), 22.6 ml (132 mmol) of di isopropyl ethylamine and 0.65 g (5.3 mmol) of 4 -dimethylaminopyridine, a solution of 5.54 g (29 mmol) of p-toluenesulphonyl chloride in 25 ml of pyridine was added dropwise over a 5 minute period. After stirring for 15 minutes at room temperature, the reaction was complete.
Det rå produkt blev direkte anvendt i det næste trin.The crude product was used directly in the next step.
^-NMR 300 MHz (i CDC13): 8 = 1,45 (3H,s); 1,92 (lH,dd); 2,18 (IH,s); 2,40 (3H,s); 2,34-2,52 (lH,m); 2,70 (lH,d); 3,15 (lH,dd); 4,06 (4H,m); 30 5,18 (lH,d); 7,28 (2H,d); 7,53 (lH,d); 7,74 (lH,t); 7,82 (2H,d); 8,28 (lH,d); 13,15 (IH,s); 13,48 (IH,s) M.S. : m/z = 582 (M+, basis top). - TLC på kieselgel plade F 254 (Merck) under anvendelse af Chloroform/acetone (8:2 ved volumen) Rf*=Q,62 351 H-NMR 300 MHz (in CDCl3): δ = 1.45 (3H, s); 1.92 (1H, dd); 2.18 (1H, s); 2.40 (3H, s); 2.34-2.52 (1H, m); 2.70 (1H, d); 3.15 (1H, dd); 4.06 (4H, m); 5.18 (1H, d); 7.28 (2H, d); 7.53 (1H, d); 7.74 (1H, t); 7.82 (2H, d); 8.28 (1H, d); 13.15 (1H, s); 13.48 (1H, s) M.S. : m / z = 582 (M +, base peak). - TLC on silica gel plate F 254 (Merck) using Chloroform / acetone (8: 2 by volume) Rf * = Q, 62 35
Eksempel 4. 4-Demethyl-4-p-methox.ybenzylamino-13-dioxolan.v1 -daunomvcinon 151Example 4. 4-Demethyl-4-p-methoxybenzylamino-13-dioxolanyl 1-daunomycinone 151
Til den i eksempel 3 opnåede opløsning, som blev holdt ved 35°C, 9 DK 170248 B1 tilsattes 101 ml (792 mmol) p-methoxybenzylamin. Reaktionsblandingen om-rørtes ved 35°C i 16 timer, afkøledes derefter til 0°C og tilsattes 4 1 methylenchlorid og 2 1 10% saltsyre. Efter adskillelse blev den organiske fase vasket med mættet vandig NaHC03 og vand. Opløsningen blev tør-5 ret over natriumsulfat og opløsningsmidlet afdampet under reduceret tryk. Remanensen blev direkte anvendt i det næste trin.To the solution obtained in Example 3 which was maintained at 35 ° C was added 101 ml (792 mmol) of p-methoxybenzylamine. The reaction mixture was stirred at 35 ° C for 16 hours, then cooled to 0 ° C and 4 L of methylene chloride and 2 L of 10% hydrochloric acid were added. After separation, the organic phase was washed with saturated aqueous NaHCO 3 and water. The solution was dried over sodium sulfate and the solvent evaporated under reduced pressure. The residue was used directly in the next step.
*H-NMR 300 MHz (i CDC13): δ = 1,50 (3H,s); 1,95 (lH,dd); 2,45 (lH,dt); 2,78 (IH,d); 3,20 (lH,bs); 3,23 (lH,dd); 3,80 (lH,bs); 3,84 (3H,s); 4,08 (4H,s); 4,53 (2H,d); 5,24 (lH,bs); 6,83 (2H,d); 7,03 (lH,d); 7,31 10 (2H,d); 7,48 (lH,t); 7,63 (lH,dd); 9,80 (lH,t); 13,47 (IH,s); 13,72 (IH,s).1 H-NMR 300 MHz (in CDCl3): δ = 1.50 (3H, s); 1.95 (1H, dd); 2.45 (1H, dt); 2.78 (1H, d); 3.20 (1H, bs); 3.23 (1H, dd); 3.80 (1H, bs); 3.84 (3H, s); 4.08 (4H, s); 4.53 (2H, d); 5.24 (1H, bs); 6.83 (2H, d); 7.03 (1H, d); 7.31 (2H, d); 7.48 (1H, t); 7.63 (1H, dd); 9.80 (1H, t); 13.47 (1H, s); 13.72 (1H, s).
TLC på kiesel gel plade F (Merck) under anvendelse af chloroform/acetone (8:2 ved volumen) Rf=0,70 M.S. : m/z = 547 (M+, basis top) 15TLC on silica gel plate F (Merck) using chloroform / acetone (8: 2 by volume) Rf = 0.70 M.S. : m / z = 547 (M +, base peak) 15
Eksempel 5. 4-Demethoxydaunomycinon (I) Råproduktet, der var udvundet som beskrevet i eksempel 4, blev opløst i 100 ml trifluoreddikesyre og omrørt i 3 timer ved stuetemperatur. Efter neutralisation blev reaktionsblandingen renset med søjlekromato-20 grafi til opnåelse af (6).Example 5. 4-Demethoxydaunomycinone (I) The crude product recovered as described in Example 4 was dissolved in 100 ml of trifluoroacetic acid and stirred for 3 hours at room temperature. After neutralization, the reaction mixture was purified by column chromatography to give (6).
2H-NMR 300 MHz (CDC13): δ = 2,14 (dd; 0=4,8; 15 Hz; IH, 8 ax. H), 2,35 (ddd; 0=2,0; 2,0; 15,0 Hz; IH, 8 eq. H), 2,45 (s, 3H, C0CH3), 2.92 (d; 0=19 Hz; IH, 10 ax. H), 25 3,17 (dd; J=2,0; 19,0 Hz; IH, 10 eq. H), 3,74 (d; 0=4,8 Hz; IH, 7-0H), 4,54 (s, IH, 9-0H), 5,32 (ddd; 0=2,0; 4,8; 4,8 Hz; IH, 7-H), 6,80 (bred, 2H, 4-NH2), 6.93 (d; 0=8,0 Hz; IH, 3-H), 30 7,46 (t; J=8,0 Hz; IH,2-H), 7,64 (d; 0=8,0 Hz; IH, 1-H), 13,52 (s, IH, 11-0H), 14,00 (s, IH, 6-OH), M.S. : m/z = 383 (M+, basis top).2 H NMR 300 MHz (CDCl 3): δ = 2.14 (dd; 0 = 4.8; 15 Hz; 1H, 8 ax. H), 2.35 (ddd; 0 = 2.0; 2.0; 15.0 Hz; 1H, 8 eq. H), 2.45 (s, 3H, COCH 3), 2.92 (d; 0 = 19 Hz; 1H, 10 ax. H), 3.17 (dd; J = 2.0; 19.0 Hz; 1H, 10 eq. H), 3.74 (d; 0 = 4.8 Hz; 1H, 7-0H), 4.54 (s, 1H, 9-0H), 5.32 (ddd; 0 = 2.0; 4.8; 4.8 Hz; 1H, 7-H), 6.80 (wide, 2H, 4-NH 2), 6.93 (d; 0 = 8.0 Hz; 1H, 3-H), 7.46 (t; J = 8.0 Hz; 1H, 2-H), 7.64 (d; O = 8.0 Hz; 1H, 1-H), 13.52 (s, 1H, 11-0H), 14.00 (s, 1H, 6-OH), MS : m / z = 383 (M +, base peak).
35 TLC på kieselgel plade F 254 (Merck) ved anvendelse af chloroform/acetone (8:2 ved volumen) Rf=0,5035 TLC on silica gel plate F 254 (Merck) using chloroform / acetone (8: 2 by volume) Rf = 0.50
Opløsningen af (6) i trifluoreddikesyre blev tilsat 2 1 methyl en- 10 DK 170248 B1 chlorid og 700 ml vand, og efter afkøling til 0°C, blev 0,93 g (13,5 mmol) natriumnitrit tilsat. Efter omrøring i 10 min blev den vandige fase fraskilt, vasket én gang med 100 ml methylenchlorid og tilsat 300 ml 50% hypophosphorsyrling og 300 ml methylenchlorid. Reaktionsbianding-5 en blev omrørt ved stuetemperatur i én time, hvorefter faserne blev adskilt. Den organiske fase blev vasket med mættet vandig NaHCOj og vand, * tørret over natriumsulfat og opløsningsmidlet blev afdampet i vakuum til opnåelse af 1,61 g (4,37 mmol) 4-demethoxydaunomycinon (I) (HPLC 92%).The solution of (6) in trifluoroacetic acid was added to 2 liters of methylene chloride and 700 ml of water and, after cooling to 0 ° C, 0.93 g (13.5 mmol) of sodium nitrite was added. After stirring for 10 minutes, the aqueous phase was separated, washed once with 100 ml of methylene chloride and 300 ml of 50% hypophosphoric acid and 300 ml of methylene chloride were added. The reaction mixture was stirred at room temperature for one hour, after which the phases were separated. The organic phase was washed with saturated aqueous NaHCO 3 and water, dried over sodium sulfate and the solvent was evaporated in vacuo to give 1.61 g (4.37 mmol) of 4-demethoxydaunomycinone (I) (HPLC 92%).
Samlet udbytte fra daunomycinon 11,5%.Total yield of daunomycinone 11.5%.
10 ^-NMR 300 MHz (CDC13): 6 = 2,19 (dd; 0=4,8; 14,5 Hz, IH, 8 ax. H), 2,37 (ddd; J=2,0; 2,0; 14,5 Hz; IH, 8 eq. H).10 NMR 300 MHz (CDCl 3): δ = 2.19 (dd; 0 = 4.8; 14.5 Hz, 1H, 8 ax. H), 2.37 (ddd; J = 2.0; 2 , 0; 14.5 Hz; 1H, 8 eq. H).
2,43 (s, 3H, COCH3), 2,95 (d; J=18,6; IH, 10 ax. H), 15 3,20 (dd; J=2,0; 18,6 Hz; IH, 10 eq. H), 3,83 (d; J=4,8 Hz; IH, 7-0H), 4,55 (s, IH, 9-OH), 5,32 (ddd; 0=2,0; 4,8; 4,8 Hz; IH, 7-H), 7,84-7,86 (m, 2H, 2,3-H), 20 8,33-8,36 (m, 2H, 1,4-H), 13,30 (s, IH, 6-OH), 13,60 (s, IH, 11-0H), U.V. spektrum (i EtOH): λ = 208, 252, 257, 285, 480, 500, 514 nm,2.43 (s, 3H, COCH 3), 2.95 (d; J = 18.6; 1H, 10 ax. H), 3.20 (dd; J = 2.0; 18.6 Hz; 1H , 10 eq. H), 3.83 (d; J = 4.8 Hz; 1H, 7-0H), 4.55 (s, 1H, 9-OH), 5.32 (ddd; 0 = 2, 0; 4.8; 4.8 Hz; 1H, 7-H), 7.84-7.86 (m, 2H, 2.3-H), 8.33-8.36 (m, 2H, 1.4-H), 13.30 (s, 1H, 6-OH), 13.60 (s, 1H, 11-0H), UV spectrum (in EtOH): λ = 208, 252, 257, 285, 480, 500, 514 nm,
Amax = 252 nm 25 I.R. Spektrum (KBr tablet) v = 3450, 1715, 1625, 1585 cm’1.Amax = 252 nm 25 I.R. Spectrum (KBr tablet) v = 3450, 1715, 1625, 1585 cm -1.
[a]p° (C = 0,1 i dioxan) = + 156°.[α] p ° (C = 0.1 in dioxane) = + 156 °.
M.S. : m/z = 368 (M+, basis top) 30 TLC på kieselgel plade F 254 (Merck) under anvendelse af chloroform/ace- tone (8:2 ved volumen) Rf=0,70. * ΛM.S. : m / z = 368 (M +, base peak) 30 TLC on silica gel plate F 254 (Merck) using chloroform / acetone (8: 2 by volume) Rf = 0.70. * Λ
Claims (10)
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| GB8803301 | 1988-02-12 | ||
| GB888803301A GB8803301D0 (en) | 1988-02-12 | 1988-02-12 | Process for preparation of 4-demethoxy-daunomycinone aglycone of 4-demethoxy-daunorubicin |
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| DK (1) | DK170248B1 (en) |
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| NZ224252A (en) * | 1987-04-21 | 1991-09-25 | Erba Carlo Spa | An anthracycline glycoside and its preparation |
| GB8808475D0 (en) * | 1988-04-11 | 1988-05-11 | Erba Carlo Spa | Process for preparing 4-demethoxydauno-mycinone |
| IT1275953B1 (en) * | 1995-03-22 | 1997-10-24 | Sicor Spa | PROCEDURE FOR THE PREPARATION OF ANTIBIOTICS OF THE CLASS OF ANTHRACYCLINES |
| AUPQ319799A0 (en) * | 1999-10-01 | 1999-10-28 | Institute Of Drug Technology Australia Limited | Chemical methods |
| US7053191B2 (en) | 2003-05-21 | 2006-05-30 | Solux Corporation | Method of preparing 4-R-substituted 4-demethoxydaunorubicin |
| ATE464280T1 (en) * | 2004-08-23 | 2010-04-15 | Sicor Inc | SYNTHESIS OF IDARUBIN-AGLYCONE |
| EP1976858B1 (en) | 2005-12-13 | 2016-01-06 | Solux Corporation | Method for preparing 4-demethyldaunorubicin |
| US8802830B2 (en) | 2005-12-20 | 2014-08-12 | Solux Corporation | Synthesis of epirubicin from 13-dihydrodaunorubicine |
| US8357785B2 (en) | 2008-01-08 | 2013-01-22 | Solux Corporation | Method of aralkylation of 4′-hydroxyl group of anthracylins |
| US8846882B2 (en) | 2011-04-29 | 2014-09-30 | Synbias Pharma Ag | Method of producing 4-demethoxydaunorubicin |
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| US3862225A (en) * | 1961-08-18 | 1975-01-21 | Pfizer | D-ring substituted tetracyclines |
| US4020270A (en) * | 1974-05-02 | 1977-04-26 | Societa' Farmaceutici Italia S.P.A. | L-lyxohex-1-enopyranose derivative |
| GB1467383A (en) * | 1974-06-12 | 1977-03-16 | Farmaceutici Italia | Daunomycin analogues |
| GB1500421A (en) * | 1975-01-22 | 1978-02-08 | Farmaceutici Italia | Optically active anthracyclinones |
| GB1509875A (en) * | 1976-06-14 | 1978-05-04 | Farmaceutici Italia | Optically active anthracyclinones and anthracycline glycosides |
| GB1527050A (en) * | 1976-06-19 | 1978-10-04 | Farmaceutici Italia | Optically active anthracyclinones |
| GB8317037D0 (en) * | 1983-06-23 | 1983-07-27 | Erba Farmitalia | 6-deoxyanthracyclines |
| US4495103A (en) * | 1982-07-30 | 1985-01-22 | Sumitomo Chemical Company, Ltd. | Preparation of optically active 4-demethoxydaunomycinone |
| JPS61501388A (en) * | 1983-10-19 | 1986-07-10 | ザ ユニヴア−シテイ オブ メルボルン | organic compounds |
| NZ224252A (en) * | 1987-04-21 | 1991-09-25 | Erba Carlo Spa | An anthracycline glycoside and its preparation |
| GB8808475D0 (en) * | 1988-04-11 | 1988-05-11 | Erba Carlo Spa | Process for preparing 4-demethoxydauno-mycinone |
| GB8824947D0 (en) * | 1988-10-25 | 1988-11-30 | Erba Carlo Spa | New 4-substituted anthracyclinones & process for preparing them |
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